Straightforward and Efficient Protocol for the Synthesis of Pyrazolo [4,3-b]pyridines and Indazoles

An efficient method for the synthesis of pyrazolo [4,3-b]pyridines has been developed on the basis of readily available 2-chloro-3-nitropyridines via a sequence of SNAr and modified Japp–Klingemann reactions. The method offers a number of advantages including utilization of stable arenediazonium tosylates, operational simplicity as well as combining the azo-coupling, deacylation and pyrazole ring annulation steps in a one-pot manner. An unusual rearrangement (C-N-migration of the acetyl group) was observed and a plausible mechanism was proposed based on the isolated intermediates and NMR experiments. In addition, the developed protocol was successfully applied to the synthesis of 1-arylindazoles combining the Japp–Klingemann reaction and cyclization of the resulting hydrazone as a one-pot procedure.


Results and Discussion
We proposed a retrosynthetic scheme for the synthesis of pyrazolo [4,3-b]pyridines, Scheme 2. The target molecules were planned to be synthesized via intramolecular nucleophilic substitution of the nitro group (S N Ar) with anions of hydrazones A which in turn could be prepared using the Japp-Klingemann reaction. The starting compounds-readily available 2-chloro-3-nitropyridines C-can be converted to pyridinyl keto esters B through a conventional S N Ar process. Such a synthetic route seemed reasonable because earlier we found that 3-NO 2 in pyridines was prone to substitution under the action of anionic O-, Nand S-nucleophiles [23]. 2-Chloro-3-nitropyridines 1a-c reacted with ethyl acetoacetate in the presence of NaH to give pyridinyl keto esters 2a-c which exist in solutions as a mixture of ketone and enol tautomers with the enol form being predominant, Scheme 3. These results are in accordance with the previously reported [24]. In the next step compound 2a was selected for screening the reaction conditions. Conventional Japp-Klingemann reaction conditions [25] were found to be unsuitable in our case: reactions of 2a with solutions of arenediazonium chlorides in the presence of sodium acetate yielded relatively stable azo-compounds 4 instead of desired hydrazones. Increasing temperature or pH only resulted in numerous side products. This prompted us to thoroughly study the azo-coupling and subsequent steps leading to target pyrazolo [4,3b]pyridines. First of all, arenediazonium tosylate 3a was prepared by a recently reported method [26] and used as an equivalent of arenediazonium chloride. These compounds are more stable than corresponding chlorides towards explosion or chemical decomposition. Arenediazonium tosylates 3 can be cleanly synthesized by diazotization of anilines in the presence of p-toluenesulfonic acid [27,28] and used without further purification, Scheme 4. Reaction of salt 3a with pyridinyl keto ester 2a under non-aqueous conditions in the presence of pyridine afforded azo-compound 4a in quantitative yield. This model Scheme 2. Retrosynthesis of pyrazolo [4,3-b]pyridines.
2-Chloro-3-nitropyridines 1a-c reacted with ethyl acetoacetate in the presence of NaH to give pyridinyl keto esters 2a-c which exist in solutions as a mixture of ketone and enol tautomers with the enol form being predominant, Scheme 3. These results are in accordance with the previously reported [24]. 2-Chloro-3-nitropyridines 1a-c reacted with ethyl acetoacetate in the presence of NaH to give pyridinyl keto esters 2a-c which exist in solutions as a mixture of ketone and enol tautomers with the enol form being predominant, Scheme 3. These results are in accordance with the previously reported [24]. In the next step compound 2a was selected for screening the reaction conditions. Conventional Japp-Klingemann reaction conditions [25] were found to be unsuitable in our case: reactions of 2a with solutions of arenediazonium chlorides in the presence of sodium acetate yielded relatively stable azo-compounds 4 instead of desired hydrazones. Increasing temperature or pH only resulted in numerous side products. This prompted us to thoroughly study the azo-coupling and subsequent steps leading to target pyrazolo [4,3b]pyridines. First of all, arenediazonium tosylate 3a was prepared by a recently reported method [26] and used as an equivalent of arenediazonium chloride. These compounds are more stable than corresponding chlorides towards explosion or chemical decomposition. Arenediazonium tosylates 3 can be cleanly synthesized by diazotization of anilines in the presence of p-toluenesulfonic acid [27,28] and used without further purification, Scheme 4. Reaction of salt 3a with pyridinyl keto ester 2a under non-aqueous conditions in the presence of pyridine afforded azo-compound 4a in quantitative yield. This model Structures of compounds 2a-c were confirmed by NMR and HRMS data. Crystal structures of 2a and 2b were determined by the X-ray diffraction analysis, Figure 2. The structure of 2a contained two crystallographically non-equivalent molecules. 2-Chloro-3-nitropyridines 1a-c reacted with ethyl acetoacetate in the presence of NaH to give pyridinyl keto esters 2a-c which exist in solutions as a mixture of ketone and enol tautomers with the enol form being predominant, Scheme 3. These results are in accordance with the previously reported [24]. In the next step compound 2a was selected for screening the reaction conditions. Conventional Japp-Klingemann reaction conditions [25] were found to be unsuitable in our case: reactions of 2a with solutions of arenediazonium chlorides in the presence of sodium acetate yielded relatively stable azo-compounds 4 instead of desired hydrazones. Increasing temperature or pH only resulted in numerous side products. This prompted us to thoroughly study the azo-coupling and subsequent steps leading to target pyrazolo [4,3b]pyridines. First of all, arenediazonium tosylate 3a was prepared by a recently reported method [26] and used as an equivalent of arenediazonium chloride. These compounds are more stable than corresponding chlorides towards explosion or chemical decomposition. Arenediazonium tosylates 3 can be cleanly synthesized by diazotization of anilines in the presence of p-toluenesulfonic acid [27,28] and used without further purification, Scheme 4. Reaction of salt 3a with pyridinyl keto ester 2a under non-aqueous conditions in the presence of pyridine afforded azo-compound 4a in quantitative yield. This model In the next step compound 2a was selected for screening the reaction conditions. Conventional Japp-Klingemann reaction conditions [25] were found to be unsuitable in our case: reactions of 2a with solutions of arenediazonium chlorides in the presence of sodium acetate yielded relatively stable azo-compounds 4 instead of desired hydrazones. Increasing temperature or pH only resulted in numerous side products. This prompted us to thoroughly study the azo-coupling and subsequent steps leading to target pyrazolo [4,3-b]pyridines. First of all, arenediazonium tosylate 3a was prepared by a recently reported method [26] and used as an equivalent of arenediazonium chloride. These compounds are more stable than corresponding chlorides towards explosion or chemical decomposition. Arenediazonium tosylates 3 can be cleanly synthesized by diazotization of anilines in the presence of p-toluenesulfonic acid [27,28] and used without further purification, Scheme 4. Reaction of salt 3a with pyridinyl keto ester 2a under non-aqueous conditions in the presence of pyridine afforded azo-compound 4a in quantitative yield. This model compound was used for the screening of various reagents that can affect deacylation and subsequent cyclization. compound was used for the screening of various reagents that can affect deacylation and subsequent cyclization. Treatment of 4a with non-nucleophilic K2CO3 resulted in decomposition signifying the importance of nucleophiles for the deacetylation step. Both NaOH and MeONa were able to yield pyrazolo [4,3-b]pyridine product although a notable side reaction with an ester group makes those reagents impractical. Milder nucleophilic bases, such as DABCO and secondary amines, all reacted cleanly to give the expected ethyl 1-(2-cyanophenyl)-6nitro-1H-pyrazolo [4,3-b]pyridine-3-carboxylate 5a along with varying amounts of the unknown compound 5a'. This compound was isolated and fully characterized by various methods including X-ray diffraction analysis ( Figure 3). It turned out to be N-aryl-Nacetylhydrazone arising from C-N migration of the acetyl group. a b Figure 3. (a) X-ray crystal structure of compound 5a' with thermal ellipsoids at a 50% probability level. Disorder of one NO2 group is omitted, (b) structural formula of 5a' To elucidate the role of compound 5a' in the course of the reaction we performed a controlled experiment with a pure sample of 4a and collected aliquots of the reaction mixture after 3, 30 and 45 min. Collected aliquots were immediately quenched with aqueous HCl, extracted and analyzed ( Figure 4). 1 H NMR spectra showed complete conversion of 4a to 5a' after 3 min with traces of 5a present. Samples taken after 30 min at 20 °C contained almost equimolar mixture of 5a' and 5a and an additional 15 min at 40 °C yielded sample with mostly pure 5a. This experiment allowed us to conclude that N-acetyl hydrazone 5a' is in fact an intermediate and can be converted to the target pyrazolo [4,3-b]pyridine under appropriate conditions. Therefore, our final protocol for the synthesis of pyrazolo [4,3b]pyridines 5 consists of azo-coupling in the presence of pyridine and subsequent one-pot cyclization by addition of pyrrolidine at 40 °C. Pyrrolidine has a favorable combination of Treatment of 4a with non-nucleophilic K 2 CO 3 resulted in decomposition signifying the importance of nucleophiles for the deacetylation step. Both NaOH and MeONa were able to yield pyrazolo [4,3-b]pyridine product although a notable side reaction with an ester group makes those reagents impractical. Milder nucleophilic bases, such as DABCO and secondary amines, all reacted cleanly to give the expected ethyl 1-(2-cyanophenyl)-6-nitro-1H-pyrazolo [4,3-b]pyridine-3-carboxylate 5a along with varying amounts of the unknown compound 5a . This compound was isolated and fully characterized by various methods including X-ray diffraction analysis ( Figure 3). It turned out to be N-aryl-N-acetylhydrazone arising from C-N migration of the acetyl group. Treatment of 4a with non-nucleophilic K2CO3 resulted in decomposition signifying the importance of nucleophiles for the deacetylation step. Both NaOH and MeONa were able to yield pyrazolo [4,3-b]pyridine product although a notable side reaction with an ester group makes those reagents impractical. Milder nucleophilic bases, such as DABCO and secondary amines, all reacted cleanly to give the expected ethyl 1-(2-cyanophenyl)-6nitro-1H-pyrazolo [4,3-b]pyridine-3-carboxylate 5a along with varying amounts of the unknown compound 5a'. This compound was isolated and fully characterized by various methods including X-ray diffraction analysis ( Figure 3). It turned out to be N-aryl-Nacetylhydrazone arising from C-N migration of the acetyl group. To elucidate the role of compound 5a' in the course of the reaction we performed a controlled experiment with a pure sample of 4a and collected aliquots of the reaction mixture after 3, 30 and 45 min. Collected aliquots were immediately quenched with aqueous HCl, extracted and analyzed ( Figure 4). 1 H NMR spectra showed complete conversion of 4a to 5a' after 3 min with traces of 5a present. Samples taken after 30 min at 20 °C contained almost equimolar mixture of 5a' and 5a and an additional 15 min at 40 °C yielded sample with mostly pure 5a. This experiment allowed us to conclude that N-acetyl hydrazone 5a' is in fact an intermediate and can be converted to the target pyrazolo [4,3-b]pyridine under appropriate conditions. Therefore, our final protocol for the synthesis of pyrazolo [4,3b]pyridines 5 consists of azo-coupling in the presence of pyridine and subsequent one-pot cyclization by addition of pyrrolidine at 40 °C. Pyrrolidine has a favorable combination of To elucidate the role of compound 5a in the course of the reaction we performed a controlled experiment with a pure sample of 4a and collected aliquots of the reaction mixture after 3, 30 and 45 min. Collected aliquots were immediately quenched with aqueous HCl, extracted and analyzed ( Figure 4). 1 H NMR spectra showed complete conversion of 4a to 5a after 3 min with traces of 5a present. Samples taken after 30 min at 20 • C contained almost equimolar mixture of 5a and 5a and an additional 15 min at 40 • C yielded sample with mostly pure 5a. This experiment allowed us to conclude that N-acetyl hydrazone 5a is in fact an intermediate and can be converted to the target pyrazolo [4,3-b]pyridine under appropriate conditions. Therefore, our final protocol for the synthesis of pyrazolo  To the best of our knowledge such a rearrangement has not been previously described, although we were able to find a few articles about similar-looking C-N acyl migration in benzeneazotribenzoylmethanes (ArCO)3C-N=NAr [29,30]. This rearrangement requires prolonged heating above 130 °C and the mechanism is believed to be heterolytic cleavage and recombination. In contrast, rearrangement in our case occurs almost instantaneously at room temperature after the addition of suitable nucleophile. We propose the following mechanism which explains the role of a nucleophilic catalyst (Scheme 5). It starts with the attack of a nucleophile on an electron-deficient N=N double bond, thus creating a negative charge on the second nitrogen atom. In turn, this atom attacks the spatially close carbonyl group with the formation of a 4-membered cycle (which is drawn to illustrate a stepwise mechanism; however, a more concerted process can take place as well) which immediately opens to yield the product of acetyl migration. Significant decrease of steric strain around the quaternary carbon atom along with formation of a stable hydrazone fragment could be considered as the main driving forces. Formation of Nacetylpyrrolidine as a by-product can also be seen on Figure 3 (peak at 3.4 ppm). Absence of this compound in the reaction mixture directly after rearrangement also points towards intramolecular reaction because the formation of N-acetylpyrrolidine is virtually irreversible under reaction conditions. To the best of our knowledge such a rearrangement has not been previously described, although we were able to find a few articles about similar-looking C-N acyl migration in benzeneazotribenzoylmethanes (ArCO) 3 C-N=NAr [29,30]. This rearrangement requires prolonged heating above 130 • C and the mechanism is believed to be heterolytic cleavage and recombination. In contrast, rearrangement in our case occurs almost instantaneously at room temperature after the addition of suitable nucleophile. We propose the following mechanism which explains the role of a nucleophilic catalyst (Scheme 5). It starts with the attack of a nucleophile on an electron-deficient N=N double bond, thus creating a negative charge on the second nitrogen atom. In turn, this atom attacks the spatially close carbonyl group with the formation of a 4-membered cycle (which is drawn to illustrate a stepwise mechanism; however, a more concerted process can take place as well) which immediately opens to yield the product of acetyl migration. Significant decrease of steric strain around the quaternary carbon atom along with formation of a stable hydrazone fragment could be considered as the main driving forces. Formation of N-acetylpyrrolidine as a by-product can also be seen on Figure 3 (peak at 3.4 ppm). Absence of this compound in the reaction mixture directly after rearrangement also points towards intramolecular reaction because the formation of N-acetylpyrrolidine is virtually irreversible under reaction conditions. The scope and limitations of the developed one-pot method was studied using compounds 2a-c and various arenediazonium tosylates, Scheme 6. Generally, reactions proceeded smoothly in the case of both electron-withdrawing and electron-releasing groups in the aryl substituent, resulting in the formation of pyrazolo [4,3-b]pyridines 5a-s in moderate to high yields. In all cases, formation of the intermediates of type 5a' was observed by TLC, N-acetyl-N-arylhydrazone 5q' was isolated and characterized by the spectral methods and Xray analysis, Figure 5. Structures of compounds 5 were confirmed by NMR and HRMS, as well as by X-ray analysis for compound 5c, Figure 5. The scope and limitations of the developed one-pot method was studied using compounds 2a-c and various arenediazonium tosylates, Scheme 6. Generally, reactions proceeded smoothly in the case of both electron-withdrawing and electron-releasing groups in the aryl substituent, resulting in the formation of pyrazolo [4,3-b]pyridines 5a-s in moderate to high yields. The scope and limitations of the developed one-pot method was studied using compounds 2a-c and various arenediazonium tosylates, Scheme 6. Generally, reactions proceeded smoothly in the case of both electron-withdrawing and electron-releasing groups in the aryl substituent, resulting in the formation of pyrazolo [4,3-b]pyridines 5a-s in moderate to high yields. In all cases, formation of the intermediates of type 5a' was observed by TLC, N-acetyl-N-arylhydrazone 5q' was isolated and characterized by the spectral methods and Xray analysis, Figure 5. Structures of compounds 5 were confirmed by NMR and HRMS, as well as by X-ray analysis for compound 5c, Figure 5. In all cases, formation of the intermediates of type 5a was observed by TLC, N-acetyl-N-arylhydrazone 5q' was isolated and characterized by the spectral methods and X-ray analysis, Figure 5. Structures of compounds 5 were confirmed by NMR and HRMS, as well as by X-ray analysis for compound 5c, Figure 5 The developed method of pyrazole ring annulation can be applied to the synthesis of indazoles from nitrobenzene derivatives. However, in the case of nitrophenyl chlorides, which are less active compared to the corresponding chloronitropyridines, reaction conditions were changed in order to reach higher yields. Thus, 4-R-1-chloro-2-nitrobenzenes 6a-d reacted with ethyl acetoacetate in the presence of K2CO3 in DMF at 60 o C to give phenyl keto esters 7a-d, Scheme 7. Compounds 7 were reacted with arenedizonium tosylates 3 under conditions elaborated for pyridyl acetoacetic esters 2a-d in a one-pot manner, Scheme 7. DBU was used as a base in case of compounds 7b-d since cyclization was found to proceed slowly in the presence of pyrrolidine. As a result, indazoles 8a-k were obtained in 60-83% yields. TLC and NMR monitoring of the reaction mixtures did not reveal formation of the intermediate N-acetyl-N-arylhydrazones, indeed, azocompounds 9 formed as a result of azo-coupling were being converted directly to hydrazones 10 which were further cyclized under the action of a base. This allowed us to propose that reactions of benzene derivatives The developed method of pyrazole ring annulation can be applied to the synthesis of indazoles from nitrobenzene derivatives. However, in the case of nitrophenyl chlorides, which are less active compared to the corresponding chloronitropyridines, reaction conditions were changed in order to reach higher yields. Thus, 4-R-1-chloro-2-nitrobenzenes 6a-d reacted with ethyl acetoacetate in the presence of K 2 CO 3 in DMF at 60 o C to give phenyl keto esters 7a-d, Scheme 7. Compounds 7 were reacted with arenedizonium tosylates 3 under conditions elaborated for pyridyl acetoacetic esters 2a-d in a one-pot manner, Scheme 7. DBU was used as a base in case of compounds 7b-d since cyclization was found to proceed slowly in the presence of pyrrolidine. As a result, indazoles 8a-k were obtained in 60-83% yields. The developed method of pyrazole ring annulation can be applied to the synthesis of indazoles from nitrobenzene derivatives. However, in the case of nitrophenyl chlorides, which are less active compared to the corresponding chloronitropyridines, reaction conditions were changed in order to reach higher yields. Thus, 4-R-1-chloro-2-nitrobenzenes 6a-d reacted with ethyl acetoacetate in the presence of K2CO3 in DMF at 60 o C to give phenyl keto esters 7a-d, Scheme 7. Compounds 7 were reacted with arenedizonium tosylates 3 under conditions elaborated for pyridyl acetoacetic esters 2a-d in a one-pot manner, Scheme 7. DBU was used as a base in case of compounds 7b-d since cyclization was found to proceed slowly in the presence of pyrrolidine. As a result, indazoles 8a-k were obtained in 60-83% yields. TLC and NMR monitoring of the reaction mixtures did not reveal formation of the intermediate N-acetyl-N-arylhydrazones, indeed, azocompounds 9 formed as a result of azo-coupling were being converted directly to hydrazones 10 which were further cyclized under the action of a base. This allowed us to propose that reactions of benzene derivatives 7 proceed according to a conventional Japp-Klingemann mechanism, Scheme 8. Hydrazone 10e was isolated and characterized to confirm the reaction scheme. 7 proceed according to a conventional Japp-Klingemann mechanism, Scheme 8. Hydrazone 10e was isolated and characterized to confirm the reaction scheme. This consistent difference in reaction pathway between pyridine and benzene derivatives does not seem to be affected by substituents, therefore the heterocyclic nitrogen atom can be considered as the main reason for the unusual reactivity. One possible explanation is hydrogen bonding between this nitrogen atom and the attacking nucleophile which would coordinate it towards the azo-group, Figure 6. Another factor could be higher steric demand of the C-H fragment, disfavoring attack on the adjacent nitrogen atom of the azo-group.

Conclusions
In summary, we have developed an efficient one-step method for the synthesis of pyrazolo [4,3-b]pyridines and indazoles on the basis of the modified Japp-Klingemann reaction and intramolecular nucleophilic substitution of the nitro group. The method comprises readily available starting materials, mild reaction conditions, easy work-up and high product yields. A plausible mechanism for the formation of both pyrazolo [4,3-b]pyridines and indazoles was proposed. As a result, a wide range of polyfunctional fused pyrazoles was synthesized which can be considered as prospective platforms for the design of pharmacology-oriented heterocyclic systems. This consistent difference in reaction pathway between pyridine and benzene derivatives does not seem to be affected by substituents, therefore the heterocyclic nitrogen atom can be considered as the main reason for the unusual reactivity. One possible explanation is hydrogen bonding between this nitrogen atom and the attacking nucleophile which would coordinate it towards the azo-group, Figure 6. Another factor could be higher steric demand of the C-H fragment, disfavoring attack on the adjacent nitrogen atom of the azo-group. 7 proceed according to a conventional Japp-Klingemann mechanism, Scheme 8. Hydrazone 10e was isolated and characterized to confirm the reaction scheme. This consistent difference in reaction pathway between pyridine and benzene derivatives does not seem to be affected by substituents, therefore the heterocyclic nitrogen atom can be considered as the main reason for the unusual reactivity. One possible explanation is hydrogen bonding between this nitrogen atom and the attacking nucleophile which would coordinate it towards the azo-group, Figure 6. Another factor could be higher steric demand of the C-H fragment, disfavoring attack on the adjacent nitrogen atom of the azo-group.

Conclusions
In summary, we have developed an efficient one-step method for the synthesis of pyrazolo [4,3-b]pyridines and indazoles on the basis of the modified Japp-Klingemann reaction and intramolecular nucleophilic substitution of the nitro group. The method comprises readily available starting materials, mild reaction conditions, easy work-up and high product yields. A plausible mechanism for the formation of both pyrazolo [4,3-b]pyridines and indazoles was proposed. As a result, a wide range of polyfunctional fused pyrazoles was synthesized which can be considered as prospective platforms for the design of pharmacology-oriented heterocyclic systems.

General Information
All chemicals were of commercial grade and used directly without purification. Melting points were measured on a Stuart SMP20 apparatus (Stuart (Bibby Scientific), Stone, UK). 1 H and 13 C NMR spectra were recorded on a Bruker AM-300 (at 300.13 and 75.13 MHz, respectively, Bruker Biospin, Ettlingen, Germany) or Bruker Avance DRX 500 (at 500 and 125 MHz, respectively, Bruker Biospin, Germany) in DMSO-d 6 or CDCl 3 . J values are given in Hz. HRMS spectra were recorded on a Bruker micrOTOF II mass spectrometer using ESI. All reactions were monitored by TLC analysis using ALUGRAM SIL G/UV254 plates, which were visualized with UV light. Compounds 1a-c and 6a-c were purchased from commercial suppliers. Compound 6d was synthesized according to the previously described procedure [31].

General Procedure for the Synthesis of Compounds 2a-c
To a stirred suspension of NaH (60% in mineral oil, 1.60 g, 40 mmol) in anhydrous THF (50 mL), ethyl acetoacetate (2.55 mL, 20 mmol) was added dropwise. The suspension was stirred for 15 min and the corresponding chloronitroarene (20 mmol) was added in small portions. The reaction mixture was stirred at 40 • C for 2-6 h (monitored by TLC), poured in 250 mL of water and acidified with conc. HCl to pH 3. The red color of the solution disappeared and an oily product started to separate, which was extracted with CHCl 3 . The organic phase was dried over anhydrous Na 2 SO 4 , evaporated and purified via column chromatography (SiO 2 /CHCl 3 ). Compounds 2a-c have a strong tendency to overcool and stay in the form of viscous oil for several weeks before sudden crystallization occurs. Compounds 2a-c exist as a mixture of ketone and enol tautomers in solutions with the enol form being dominant, thus only NMR data for the enol form were provided below, while compound names correspond to keto tautomers for clarity.

General Procedure for the Synthesis of Compounds 7a-d
The corresponding chloronitroarene (20 mmol) and ethyl acetoacetate (3.19 mL, 25 mmol) were dissolved in 35 mL of DMF then anhydrous K 2 CO 3 (5.52 g, 40 mmol) was added and the reaction mixture was stirred at 60 • C for 2-6 h (monitored by TLC), poured in 150 mL of water and acidified with conc. HCl to pH 3. The product was extracted with CHCl 3 , the combined organic phase was dried over anhydrous Na 2 SO 4 , evaporated and purified via column chromatography (SiO 2 /CHCl 3 ). Compounds 7a-d have a strong tendency to overcool and stay in the form of viscous oil for several weeks before sudden crystallization occurs. Compounds 7 exist as a mixture of ketone and enol tautomers in solutions with the enol form being dominant, thus only NMR data for the enol form are provided below, while compound names correspond to keto tautomers for clarity.

General Procedure for the Synthesis of Aryldiazonium Tosylates 3 [26]
Although aryldiazonium tosylates are generally considered to be relatively safe compared to other aryldiazonium salts, and no incidents occurred during this work, these compounds should be handled with appropriate precautions.
TsOH*H 2 O (2.28 g, 12 mmol) was dissolved in ethyl acetate (50 mL) and the appropriate aniline (8 mmol) was added. The suspension of anilinium tosylate was stirred for 10 min and iPrONO (2.46 mL, 24 mmol) was added in one portion. The amine salt disappeared and a new precipitate of diazonium salt started to form. The reaction mixture was stirred at room temperature (r.t.) for 2 h and filtered. Diazonium salts were washed with Et 2 O, dried in air and used as is. Yields 67-93%. 2-Methoxyphenyldiazonium tosylate failed to crystallize and was used as oil. These salts can be stored at room temperature for a week with minor discoloration and no visible decomposition was observed after 3 months of storage in a freezer.

Synthesis of the Intermediates 4a, 5a and 5q
To a solution of compound 2a (0.32 g, 1 mmol) in MeCN (5 mL) 2-cyanophenyldiazonium tosylate (1.1 mmol) was added followed by pyridine (0.08 mL, 1 mmol). The reaction mixture was stirred at r.t. for 30 min (monitored by TLC) then poured in 50 mL of water, acidified to pH 3 with conc. hydrochloric acid and extracted with CHCl 3 . Combined organic phase was dried over anhydrous Na 2 SO 4 , evaporated and the residue was purified by column chromatography (SiO 2 /CHCl 3 ).
In the case of compounds 7b and 7c, pyridine was substituted for 0.45 mL (3 mmol) of DBU and the amount of pyrrolidine was reduced to 1 mmol.

Conclusions
In summary, we have developed an efficient one-step method for the synthesis of pyrazolo [4,3-b]pyridines and indazoles on the basis of the modified Japp-Klingemann reaction and intramolecular nucleophilic substitution of the nitro group. The method comprises readily available starting materials, mild reaction conditions, easy work-up and high product yields. A plausible mechanism for the formation of both pyrazolo [4,3-b]pyridines and indazoles was proposed. As a result, a wide range of polyfunctional fused pyrazoles was synthesized which can be considered as prospective platforms for the design of pharmacology-oriented heterocyclic systems.